Browsing by keyword "p38 MAPK"

Now showing items 1-2 of 2

    • Involvement of p38-betaTrCP-Tristetraprolin-TNFalpha axis in radiation pneumonitis
      Krishnamurthy, Pranathi Meda; Shukla, Shirish; Ray, Paramita; Mehra, Rohit; Nyati, Mukesh K.; Lawrence, Theodore S.; Ray, Dipankar (2017-07-18)
      Early release of tumor necrosis factor-alpha (TNF-alpha) during radiotherapy of thoracic cancers plays an important role in radiation pneumonitis, whose inhibition may provide lung radioprotection. We previously reported radiation inactivates Tristetraprolin (TTP), a negative regulator of TNF-alpha synthesis, which correlated with increased TNF-alpha release. However, the molecular events involved in radiation-induced TTP inactivation remain unclear. To determine if eliminating Ttp in mice resulted in a phenotypic response to radiation, Ttp-null mice lungs were exposed to a single dose of 15 Gy, and TNF-alpha release and lung inflammation were analyzed at different time points post-irradiation. Ttp-/- mice with elevated (9.5+/-0.6 fold) basal TNF-alpha showed further increase (12.2+/-0.9 fold, p < 0.02) in TNF-alpha release and acute lung inflammation within a week post-irradiation. Further studies using mouse lung macrophage (MH-S), human lung fibroblast (MRC-5), and exogenous human TTP overexpressing U2OS and HEK293 cells upon irradiation (a single dose of 4 Gy) promoted p38-mediated TTP phosphorylation at the serine 186 position, which primed it to be recognized by an ubiquitin ligase (E3), beta transducing repeat containing protein (beta-TrCP), to promote polyubiquitination-mediated proteasomal degradation. Consequently, a serine 186 to alanine (SA) mutant of TTP was resistant to radiation-induced degradation. Similarly, either a p38 kinase inhibitor (SB203580), or siRNA-mediated beta-TrCP knockdown, or overexpression of dominant negative Cullin1 mutants protected TTP from radiation-induced degradation. Consequently, SB203580 pretreatment blocked radiation-induced TNF-alpha release and radioprotected macrophages. Together, these data establish the involvement of the p38-betaTrCP-TTP-TNFalpha signaling axis in radiation-induced lung inflammation and identified p38 inhibition as a possible lung radioprotection strategy.

    • p38alpha MAPK is required for tooth morphogenesis and enamel secretion
      Greenblatt, Matthew B.; Kim, Jung-Min; Oh, Hwanhee; Park, Kwang Hwan; Choo, Min-Kyung; Sano, Yasuyo; Tye, Coralee E.; Skobe, Ziedonis; Davis, Roger J.; Park, Jin Mo; et al. (2015-01-02)
      An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38alpha MAPK in ectodermal appendages using K14-cre mice (p38alpha(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38alpha, expression of amelogenin and beta4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38alpha in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38alpha functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38alpha MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.